While bone tissues have regenerative capabilities that enable self-repair of fractures, in extreme cases complete critical defect healing will not occur. Such bone defects in the craniofacial complex are often a result of birth defects, trauma or cancer surgery. Unfortunately, the long- term results of craniomaxillofacial reconstructions are very poor due to the overwhelming tissue fibrosis and scarring that occurs following surgery. This inflammatory-foreign body response to the grafted biomaterial remains one of the great challenges in treating these patients. To address this, our multi-institutional investigative team has sustained a long-term collaboration that produced several advances in this field including extraordinary success in treating several patients with facture non-unions non-surgically with recombinant parathyroid hormone (rPTH, teriparatide). To elucidate the mechanisms responsible for these rPTH effects on bone healing, and translate it to a Musculoskeletal Tissue Engineering (MTE) solution for critical bone defects, we published several preclinical discoveries. The most relevant to this renewal application are: 1) angiopoietins (Ang) 1 & Ang-2, which regulate large vessel vasculogenesis, are reciprocally regulated by rPTH therapy to inhibit large blood vessels proximal to the allograft; and 2) rPTH also inhibits the accumulation of pro-fibrotic mast cells adjacent to the large vessels. Based on this we hypothesize that rPTH therapy facilitates critical defect healing by: 1) its well-known anabolic effects on osteoblasts (Col1(2.3)+) to increase bone healing beyond the limits of a critical defect, 2) osteoblast-induced small vessel angiogenesis at the healing front, and 3) inhibitory effects on large vessel vasculogenesis, mast cell accumulation and fibrosis. Technologically, we: 1) developed a chronic cranial defect window chamber model for in vivo multiphoton laser scanning microscopy (MPLSM); 2) established a clinically relevant model of critical defect healing in the minipig mandible: 3) developed custom 3D-printed bone scaffolds to replace massive allografts; and 4) developed autologous osteogenic-iPS cells (iMSC) with enhanced bone forming properties and reduced transformation potential. Here we propose to use these innovative technologies to: 1) test our hypotheses on the nature of critical defects in craniofacial bones, 2) formally elucidate the mechanism by which rPTH therapy inhibits inflammation and fibrosis to allow for critical craniomaxillofacial bone defect healing, and 3) provide a translational MTE solution for this challenging clinical problem in a large animal model. Given the high clinical relevance of these proofs of concept, the potential impact of success could be huge for this significant problem.